Abstract The World Health Organization has recognized a global pandemic of novel coronavirus pneumonia (COVID-19) from exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses (CoVs) are membrane-enveloped positive-sense, single-stranded RNA viruses decorated with membrane proteins. The spike (S) glycoprotein is implicated in the viral attachment and fusion to host cells via the human angiotensin- converting enzyme 2 (hACE2). There are different assays to test for COVID-19, including nucleic acid, antigen, and serological tests that can be used in hospitals, point-of-care, and large-scale population testing. Nucleic acid testing is the standard method for the detection of SARS-CoV-2, which consists of the amplification of viral RNA from nasopharyngeal swabs (NPS) by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Furthermore, given the invasive nature of NPS, saliva is being considered an alternative for detection. Methods that bypass RNA extraction, as well as isothermal amplification such as loop-mediated isothermal amplification (LAMP), have been developed to improve the speed of viral RNA detection. However, viral protein expression cannot be detected by qRT-PCR. Serological tests, on the other hand, are based on host antibodies against the virus (IgG/IgM). Although fast, these tests suffer from significant false negative/positive. Besides, they do not detect a current infection. Therefore, to relieve the current healthcare crisis, new technologies capable of simultaneous viral RNA/protein detection at the single virus level and host antibody response detection from a body fluid in an integrated device would be highly valuable for enhanced COVID-19 diagnosis. Recently, our group, as part of Phase 2 of the Extracellular RNA Communication Consortium (ERCC2), has successfully developed a microfluidics technology capable of capturing individual exosomes from biofluids and then simultaneously quantify both exosomal surface proteins and RNA cargo. Given the resemblance in size and other characteristics between exosomes and coronaviruses, our technology can be adapted for COVID-19 diagnosis. Therefore, we propose to develop and validate a safe-to-use version of our microfluidics system for direct detection of SARS-CoV-2. The integrated system is capable of multi-parametric detection for enhanced COVID-19 diagnosis. The platform will be engineered to simultaneously quantify both viral protein, viral RNA, and host antibodies (IgG/IgM) in the same sample, enabling diagnosis, disease status, and prognostic assessment. Model systems, including host IgG/IgM from patient serum, standard synthetic vesicles (SVs), and heat-inactivated SARS-CoV-2 viral particles (SVVs), will be designed and spiked in biofluids to validate and calibrate the system. To demonstrate the clinical utility, our biochip technology will be deployed and tested using different biofluids from COVID-19 patients at two independent ...